Review

In 1985, Parry and Clarke

1
studied nerve conduction in
two patients with a lower-motor-neuron syndrome
characterised by progressive, asymmetric, pre-
dominantly distal weakness without sensory loss and
found conduction block. Soon afterwards, others
reported patients with similar characteristics.
2,3
Weakness in patients with a lower-motor-neuron
syndrome with conduction block was shown to be
reversible with immunomodulating therapy and
associated with high titres of IgM antibodies to GM1
ganglioside.
4
Hence, a separate disorder emerged:
multifocal motor neuropathy (MMN).
411
The disorder
was thought to be immune mediated, possibly through
IgM antibodies that bind gangliosides on human
peripheral nerves.
12
The differential diagnosis of MMN
includes motor-neuron disease
13,14
and demyelinating
neuropathies.
1517
Diagnosis of MMN is supported by the
nding of motor but not of sensory abnormalities on
nerve-conduction studies.
1823
Whether conduction block
must be present for the diagnosis of MMN is debatable.
Various open and placebo-controlled studies have shown
that treatment with high-dose intravenous immuno-
globulin leads to improvement of muscle strength.
Intravenous immunoglobulin is now the treatment of
rst choice in MMN.
2427
Many clinical and
electrophysiological studies have improved our
understanding of MMN in the past 15 years, but the
disease mechanisms underlying weakness in MMN are
poorly understood.
Clinical features
MMN is characterised by slowly progressive weakness
and muscle atrophy that develops gradually over several
years.
8,11,22,23,2831
More men than women are affected, at a
ratio of 26. The mean age at onset is 40 years, with a
range of 2070 years.
9,22,32
In almost 80% of patients, the
rst symptoms occur between age 20 years and 50 years.
The most common initial symptoms are wrist drop, grip
weakness, and foot drop. Weakness develops
asymmetrically and is more prominent in the arms than
in the legs.
22,23
In most patients with onset in the legs, the
abnormalities also eventually affect the arms and
become the most prominent.
33
Symptoms and signs in
the distal muscles prevail for a long time, but eventually
weakness in proximal muscle groups of the arms, but
not of the legs, may develop.
32,33
Weakness is typically
more pronounced than the degree of atrophy
suggests.
11,22
Nevertheless, atrophy of affected muscles
can be substantial in patients with a long disease
duration. Other motor symptoms include muscle
cramps and fasciculations in about two-thirds
of patients.
3,19,21
Myokymia has been reported
occasionally.
3,19,21
Tendon reexes are commonly reduced
in affected regions, although these are rarely brisk in the
arms.
4,21,22,28,30
Single cases of cranial-nerve involvement
have been reported.
21,3436
Respiratory failure due to
unilateral or bilateral phrenic-nerve palsy can occur,
even at the beginning of the disorder.
35,37,38
Some patients
report feelings of paraesthesia or numbness but sensory
loss on objective neurological or neurophysiological
assessment should not be found.
Differential diagnosis
The differential diagnosis of MMN includes two
different categories of disorders: motor-neuron
disease
2,13,14,28,3943
and demyelinating neuropathies.
1517
The rst signs and symptoms in MMN can be similar to
those in motor-neuron disease, and some patients are
initially diagnosed as having amyotrophic lateral
sclerosis or lower-motor-neuron disease.
13,14
The slowly
progressive disease course, the absence of upper-motor-
neuron signs or bulbar signs and the presence of
demyelinating features on electrodiagnostic assessment
will eventually differentiate MMN from amyotrophic
lateral sclerosis; differentiation of MMN from lower-
motor-neuron disease is more difcult. We
14
categorised
lower-motor-neuron disease into four types of spinal
muscular atrophy: slowly progressive general; distal;
segmental distal; and segmental proximal. Clinically,
MMN is difcult to differentiate from slowly progressive
generalised spinal muscular atrophy or segmental distal
spinal muscular atrophy.
14,44
The nding of persistent
motor-nerve conduction block on nerve-conduction
studies outside nerve compression sites, a positive titre
Lancet Neurol 2005; 4: 30919
Department of Clinical
Neurophysiology
(J-T H Van Asseldonk MD,
H Franssen PhD) and
Department of Neurology
(R M Van den Berg-Vos PhD,
J H J Wokke PhD,
L H Van den Berg PhD),
Neuromuscular Research
Group, Rudolf Magnus Institute
of Neuroscience, University
Medical Centre Utrecht,
Netherlands
Correspondence to:
Dr Leonard H Van den Berg,
Department of Neurology,
University Medical Centre
Utrecht, PO Box 85500,
Heidelberglaan 100, 3584 CX
Utrecht, Netherlands
l.h.vandenberg@neuro.azu.nl
http://neurology.thelancet.com Vol 4 May 2005 309
Multifocal motor neuropathy (MMN) is an immune-mediated disorder characterised by slowly progressive,
asymmetrical weakness of limbs without sensory loss. The clinical presentation of MMN mimics that of lower-
motor-neuron disease, but in nerve-conduction studies of patients with MMN motor-conduction block has been
found. By contrast with chronic inammatory demyelinating polyneuropathy, treatment with prednisolone and
plasma exchange is generally ineffective in MMN and even associated with clinical worsening in some patients. Of
the immunosuppressants, cyclophosphamide has been reported as effective but only anecdotally. Various open trials
and four placebo-controlled trials have shown that treatment with high-dose intravenous immunoglobulin leads to
improvement of muscle strength in patients with MMN. Although clinical, pathological, imaging, immunological,
and electrophysiological studies have improved our understanding of MMN over the past 15 years, further research
is needed to elucidate pathogenetic disease mechanisms in the disorder.
Multifocal motor neuropathy
Jan-Thies H Van Asseldonk, Hessel Franssen, Renske M Van den Berg-Vos, John H J Wokke, Leonard H Van den Berg
Review
of anti-GM1, or high signal intensity on T2-weighted
MRI of the brachial plexus can help to differentiate
MMN from lower-motor-neuron disease.
45
Within the demyelinating neuropathies, the disorders
from which MMN must be differentiated are: chronic
inammatory demyelinating polyneuropathy (CIDP),
particularly the pure motor form, and the Lewis-Sumner
syndrome.
16,17,4653
In patients with CIDP, proximal
symmetrical weakness and general areexia are
common, whereas weakness in MMN is asymmetrical
and distal, and reexes are only poor or absent in
affected limbs. A remitting and relapsing course or a
progression of symptoms in weeks is common in CIDP
but not in MMN. The CSF protein concentration in
MMN is normal or slightly increased but rarely higher
than 1 g/L, unlike in CIDP, and can therefore help to
differentiate between the two.
11,23,45
Sensory signs and
symptoms also differ for MMN and CIDP. On nerve-
conduction studies, motor conduction block is found in
both disorders, but other features of demyelination are
more prominent in CIDP, such as slowed conduction
velocities and prolonged distal latencies.
23,46
Another
disease entity that has similarities with MMN (and
CIDP) is the Lewis-Sumner syndrome (table 1).
4853
Patients with this syndrome have an asymmetrical
sensory or sensorimotor demyelinating neuropathy that
can be localised to one arm or leg for several years,
sometimes associated with neuropathic pain or focal
nerve tenderness. Nerve-conduction studies are
necessary to diagnose the syndrome and can help to
differentiate it from MMN because low action-potential
amplitudes in distal sensory nerves are found in many
patients with the Lewis-Sumner syndrome, but not in
patients with MMN. Patients with the Lewis-Sumner
syndrome can benet from treatment with
corticosteroids, whereas those with MMN do not, and
can even deteriorate.
21,34,5457
Diagnosis
Electrophysiological characteristics
Conduction block, the failure of a nerve impulse to
propagate through a structurally intact axon, is the
electrophysiological hallmark of MMN in motor
conduction studies (gure 1).
1,4,1823,28,58
Conduction block
in a sufcient number of axons can be detected as a
lower amplitude or area of the compound muscle action
potential (CMAP) on proximal stimulation of a nerve
segment than on distal stimulation of that segment
(proximal/distal decrement in CMAP; gure 1). As well
as conduction block, two other mechanisms can lead to
CMAP decrement.
59,60
When axons within a nerve have
different conduction times (known as temporal
dispersion), the positive phase of fast-motor-unit action
potentials coincides with the negative phase of slow-
motor-unit action potentials, yielding increased duration
of the proximal compared with the distal CMAP, phase
cancellation, and CMAP decrement. Furthermore,
polyphasia of the motor-unit action potentials that
contribute to the CMAP (due to collateral sprouting) has
been assumed to yield increased phase cancellation and,
consequently, a greater CMAP decrement. Because the
occurrence of temporal dispersion and polyphasic
motor-unit action potentials can yield CMAP decrement
and mimic conduction block in peripheral
polyneuropathies and lower-motor-neuron disease,
61,62
criteria to separate conduction block from the other
mechanisms that can cause CMAP decrement are
needed. A simulation study in rats, in which compound
muscle-unit action potentials were reconstructed from
motor-unit action potentials, showed that maximum
temporal dispersion could result in a decrement of the
CMAP area of up to 50%.
59
No simulation studies with
human polyphasic motor-unit action potentials and
realistic temporal dispersion have been done.
Consequently, a decrease in the CMAP area of more
than 50% is currently the best indication that conduction
is blocked in one or more axons of a nerve. Evidence is
lacking for various other criteria for conduction block,
which are based on expert opinions that have been
established by consensus.
45,60,6366
Whether conduction block is always part of MMN is an
important issue and depends on the criteria for
conduction block and the number of nerves investigated.
We reviewed studies in which patients with lower-motor-
neuron syndromes were treated with intravenous
immunoglobulin, to assess whether or not conduction
block was present (table 2). In nerves with limited
temporal dispersion (30%), a criterion consisting of a
CMAP (area or amplitude) decrement of at least 50% was
fullled in none,
67
or in few patients who responded
positively to intravenous immunoglobulin.
20
This number
increased when conduction block criteria allowed more
temporal dispersion, required less CMAP decrement, or a
combination of both.
20,45
The American Academy of
Electrodiagnostic Medicine proposed research criteria
310 http://neurology.thelancet.com Vol 4 May 2005
MMN Lower-motor- CIDP Lewis-Sumner
neuron disease syndrome
Distribution Asymmetrical Asymmetrical Symmetrical Asymmetrical
Arms legs Yes Yes No Yes
Prominent sensory symptoms No No Yes Yes
Reex pattern Decreased in Decreased in General areexia Decreased in
affected regions affected regions affected regions
Disease course Slowly Slowly Progressive Progressive
progressive progressive or relapsing or relapsing
Laboratory features
CSF protein 1 g/L No No Yes Rare
Anti-GM1 antibodies 3050% of patients 10% of patients Rare No
Abnormal MRI of brachial plexus Asymmetrical* No Symmetrical Asymmetrical*
Response to treatment
Intravenous immunoglobulin Yes No Yes Yes
Corticosteroids No No Yes Yes
*Corresponding with neurological decit; deterioration can occur.
52
Table 1: Comparison of typical features of MMN, lower-motor-neuron disease, CIDP, and the Lewis-
Sumner syndrome
Review
that specied the degree of temporal dispersion for nerves
and for segments within nerves, and they found
conduction block in 6070% of patients with a favourable
response to intravenous immunoglobulin.
45,68
Criteria less
stringent than those proposed by the American Academy
of Electrodiagnostic Medicine, requiring a compound-
muscle-action-potential area decrement of at least 50% in
arm or leg nerves, or a compound-muscle-action-potential
amplitude decrement of at least 30% in arm nerves, were
fullled in all patients with a favourable response to
intravenous immunoglobulin when a large number of
arm and leg nerves, including those innervating non-
weakened muscles, were studied bilaterally.
23,45
For this
reason we prefer criteria for conduction block that require
a CMAP area decrement of at least 50% or a CMAP
amplitude decrement of at least 30%. These criteria were
not fullled in all patients with a favourable response to
intravenous immunoglobulin when a small number of
arm and leg nerves were studied unilaterally.
69
In MMN,
conduction block according to these criteria is most likely
to be found in long arm nerves that innervate weakened
muscles. If conduction block cannot be found in these
nerves in patients with a lower-motor-neuron syndrome,
electrophysiological assessment should be extended to
other nerves, including long, intermediate, or short arm
nerves innervating weakened or non-weakened muscles
http://neurology.thelancet.com Vol 4 May 2005 311
Duration
(ms)
Amplitude
(mV)
Area
(mV/
ms)
Distal motor latency (ms)
Motor conduction
velocity (m/s)
Distal motor latency (ms)
Motor conduction
velocity (m/s)
Wrist 62 67 233 32
Elbow d 63 62 219 55
Elbow p 60 64 216 55
Axilla 48 14 44 23
Erb 48 19 49 58
Duration
(ms)
Amplitude
(V)
Sensory conduction
velocity (m/s)
Wrist 08 433 56
Elbow d 08 251 61
Elbow p 09 216 77
Axilla 10 181 64
Duration
(ms)
Amplitude
(mV)
Area
(mV/
ms)
Wrist 51 80 215 43
Elbow p 104 50 177 54
Axilla 124 26 179 49
Erb 145 25 177 51
5 mV
5 ms
Axilla
Elbow p
Elbow d
Wrist
Erb
Axilla
Elbow p
Wrist
5 mV
5 ms
2 ms
20 V
Axilla
Elbow p
Elbow d
Wrist
Erb
Figure 1: Conduction studies in patients with MMN
Motor conduction (left) and sensory conduction (middle) in the ulnar nerve, recorded from the fth abductor digiti muscle. Denite conduction block (a decrease of more than 50% in the CMAP area)
and motor conduction velocity compatible with demyelination were found in the upper arm segment. No abnormalities in sensory conduction were found. Motor conduction in the median nerve of a
different patient (right) recorded from the left and middle abductor pollicis brevis muscle. Increased temporal dispersion (a prolongation of more than 30% in the CMAP duration) and probable
conduction block (a decrease of more than 30% in the CMAP amplitude) were found in the lower arm segment and probable conduction block was found in the upper arm segment. Elbow
d=stimulation 5 cm distally from elbow; elbow p=stimulation 5 cm proximally from elbow.
23
Review
on both sides, until conduction block is found.
23
Because
no favourable response to immune-modulating treatment
has ever been reported for a patient with a lower-motor-
neuron syndrome without conduction block, on extensive
nerve-conduction studies we restrict treatment to patients
with conduction block.
The detection of conduction block can be further
improved by fatiguability testing
70
or root stimulation,
70,71
both of which show conduction block in nerves in which
it is not found on conventional nerve-conduction studies
in a restricted number of nerves. Motor conduction is
typically slow in MMN, as it is in CIDP and sporadically
in motor-neuron disease.
23,46,72
Sensory-nerve-conduction
studies are needed to exclude sensory abnormalities (at
the site of conduction block) in MMN and can help to
differentiate MMN from CIDP. Low distal CMAP
amplitudes on nerve conduction studies, suggestive of
axonal degeneration, as well as signs of denervation and
re-innervation on needle electromyography, occur in
MMN, lower-motor-neuron disease, and CIDP.
46,7375
Because of axonal degeneration in MMN, needle
electromyography cannot differentiate between MMN
and lower-motor-neuron disease. Nerve-conduction
studies in patients with a lower-motor-neuron syndrome
are therefore important.
Laboratory characteristics
Results of routine analysis of blood and urine are
unremarkable in patients with MMN, despite slightly to
moderately high serum creatine-kinase activity,
consistent with slowly progressive axonal degeneration,
in up to two-thirds of patients.
45,76
In MMN, oligoclonal
bands are not found in the CSF and the IgG index is
normal.
19
Immunoxation electrophoresis is typically
normal in MMN; if a monoclonal spike is seen, the
disease should be differentiated from polyneuropathy
associated with monoclonal gammopathy of unknown
signicance. Serum immunoglobulin concentrations are
high in some patients, but they are polyclonal.
4,12,21,28,40,45,77
Initial reports of increased antibodies to GM1
ganglioside in patients with a lower-motor-neuron
syndrome and conduction block in nerve-conduction
studies raised hopes for a diagnostic marker for
MMN.
4,22,30,39,7779
Positive ndings for polyclonal anti-GM1
in about half of the patients with MMN (range 2285%),
as well as in patients with lower-motor-neuron disease,
amyotrophic lateral sclerosis, and CIDP, and even in
healthy people, suggested that the sensitivity and
specicity of antibody testing are limited.
24,77,8085
However,
in healthy people and patients with disorders other than
MMN, the titres of anti-GM1 are typically much lower
than in MMN. Several studies have shown that high titres
of IgM anti-GM1 are found in patients with Guillain-
Barr syndrome, MMN, or lower-motor-neuron
disease.
81,8688
Furthermore, a positive IgM anti-GM1 test
was associated with MMN within a group of patients with
lower-motor-neuron syndrome.
45
Moreover, a meta-
analysis on the diagnostic value of IgM anti-GM1 in
MMN showed that probabilities before the test between
20% and 60% for having MMN on the basis of clinical
characteristics changed to probabilities between 50% and
85% when IgM anti-GM1 was found.
89
Overall, these
studies show that a positive test in a patient with a lower-
motor-neuron syndrome is supportive but not conclusive
of a diagnosis of MMN and should prompt extensive
electrophysiological assessment, whereas a negative test
has no diagnostic value.
Neuroimaging
In patients with MMN, signal intensity on T2-weighted
images of the brachial plexus was asymmetrical and
high, corresponding with the distribution of
312 http://neurology.thelancet.com Vol 4 May 2005
Reference Number Standard protocol Conduction block criteria Number of Positive response to treatment with intravenous
of patients patients with immunoglobulin/total treated
Nerves investigated Bilateral CMAP decrement Duration of
conduction block
With Without
prolongation conduction block conduction block
20 16 Med, Uln, Per, Tib Unknown Amplitude and area 50% 30% 5 2/3 0/2
30% 6 4/4
23 39* Med, Uln, Rad, Mef, Mus, Per, Tib Yes Area 50% 30 30/30
Amplitude 30% 9 9/9
42 10 Med, Uln, Per, Tib No Amplitude and area 50% 30% 0 4/10
45 37 Med, Uln, Rad, Mef, Mus, Per, Tib Yes Area 50% 21 17/21 0/4
amplitude 30% 12 6/12
67 5 Unknown Unknown Amplitude 50% 15% 0 3/4
68 23 Med, Uln, Per, Tib No AAEM AAEM 14 12/14 1/3
AAEM 10% AAEM 6 4/6
69 9 Med, Uln, Rad, Mus, Per, Tib No Amplitude or area 30% 0 3/6
Med=median nerve recorded from abductor pollicis brevis; Uln=ulnar nerve recorded from fth abductor digiti; Rad=radial nerve recorded from extensor carpi ulnaris; Mef=median nerve recorded from exor carpi radialis;
Mus=musculocutaneus nerve recorded from biceps brachii; Per=deep peroneal nerve recorded from extensor digitorum brevis; Tib=tibial nerve recorded from abductor hallucis. AAEM=criteria proposed by the American
Academy of Electrodiagnostic Medicine; AAEM 10%=criteria that require 10% less decrement in amplitude on proximal versus distal stimulation or area for conduction block than those proposed by the AAEM. *Patients with a
positive response to intravenous immunoglobulin were selected, 33 patients were previously reported in a study by Van den Berg-Vos 2001.
45
Patients with conduction block or other features of demyelination on nerve
conduction studies were selected; patients were selected on the absence of conduction block.
Table 2: Presence of conduction block in patients with lower-motor-neuron syndromes who were treated with intravenous immunoglobulin
Review
symptoms.
23,45,90
Asymmetrically high signal intensity
was also shown on T1-weighted images after gadolinium
enhancement, which colocalised with conduction block
in the brachial plexus
91
and in the forearm segment of
the median nerve.
92
The ndings in MMN resemble the
symmetrical high signal intensity seen in CIDP and
might be due to demyelination.
90,93
MRI might help to
differentiate MMN from lower-motor-neuron disease;
although MRI is normal in the latter, signal intensity is
high in about 4050% of patients with MMN.
90
Diagnostic criteria
Most diagnostic studies of MMN have focused on the
diagnostic yield of criteria for conduction block, whereas
there are few data on the additional diagnostic value of
clinical and laboratory characteristics. We found that not
only the presence of conduction block, but also the age at
onset, number of affected limb regions, high signal
intensity on T2-weighted images of the brachial plexus,
and high titres of anti-GM1 predicted a positive response
to intravenous immunoglobulin treatment in patients
with lower-motor-neuron syndromes.
45
From these
ndings, we proposed a set of criteria, consisting of
combined clinical, laboratory, and electrophysiological
characteristics, for denite, probable, and possible MMN
(panel).
45
In a group of patients with lower-motor-neuron
syndromes and conduction block or conduction slowing
compatible with demyelination on nerve-conduction
studies, the likelihood of responding to intravenous
immunoglobulin treatment was 81% for denite MMN,
71% for probable MMN, and 11% for possible MMN.
45
Because our criteria improved the identication of
patients who might respond favourably to intravenous
immunoglobulin, they were proposed for clinical
practice but should be validated further.
45
Pathophysiology
Pathological, immunological, and electrophysiological
studies have improved understanding of the typical
pattern of weakness (asymmetrical, predominantly distal,
more in arm than in leg muscles), the presence of
weakness in atrophic and in non-atrophic muscles, the
absence of sensory involvement, the partial reversibility of
weakness after intravenous immunoglobulin treatment,
the poor effect of treatment as the disease progresses, the
slowly progressive course despite long-term treatment,
and the presence of IgM anti-GM1 in some patients.
Biopsy
Reluctance to take biopsy samples from motor nerves has
resulted in few pathological studies in MMN. In an ulnar-
nerve biopsy at the site of previously documented
conduction block, Auer and colleagues
94
reported onion-
bulb formation, which is characteristic of several episodes
of demyelination and remyelination, and axons that were
thinly myelinated in relation to axon diameter.
Furthermore, Kaji and colleagues
92
showed large-diameter
axons almost devoid of myelin in the median pectoral
nerve with CMAP decrement on intraoperative recording.
By contrast, Taylor and colleagues
95
showed that
multifocal loss and degeneration of axons, as well as
prominent clusters of regenerating axons, dominated over
myelin pathology in biopsy samples of motor fascicular
nerve with evidence of conduction block on intraoperative
http://neurology.thelancet.com Vol 4 May 2005 313
Panel: Proposed diagnostic criteria for MMN
Clinical criteria
1. Slow or stepwise progressive limb weakness
2. Asymmetrical limb weakness
3. Fewer than seven affected limb regions (upper arm, lower arm, upper leg, or lower leg
on both sides of body; maximum eight)
4. Tendon reexes in affected limbs are decreased or absent
5. Signs and symptoms are more pronounced in arms than in legs
6. Age 2065 years at onset of disease
7. No objective sensory abnormalities except for vibration sense
8. No bulbar signs or symptoms
9. No upper-motor-neuron features
10. No other neuropathies (eg, diabetic, lead, porphyric, or vasculitic neuropathy, CIDP,
Lyme neuroborreliosis, post-radiation neuropathy, hereditary neuropathy with liability to
pressure palsies, Charcot-Marie-Tooth neuropathies, meningeal carcinomatosis)
11. No myopathy (eg, facioscapulohumeral muscular dystrophy, inclusion-body myositis)
Laboratory criteria
1. CSF protein 1 g/L
2. High anti-GM1 titre
3. High signal intensity on T2-weighted MRI of the brachial plexus
Electrodiagnostic criteria
1. Denite motor conduction block: CMAP area reduction on proximal versus distal
stimulation of at least 50% over a long segment (between erb and axilla, upper arm, lower
arm, lower leg), or a CMAP amplitude reduction on proximal versus distal stimulation of at
least 30% over a short distance (25 cm) detected by inching. CMAP amplitude on
stimulation of the distal part of the segment with motor conduction block of at least 1 mV
2. Probable motor conduction block: CMAP amplitude reduction on proximal versus distal
stimulation of at least 30% over a long segment of an arm nerve. CMAP amplitude on
stimulation of the distal part of the segment with motor conduction block of at least 1 mV
3. Slowing of conduction compatible with demyelination: MCV 75% of the lower limit of
normal; DML or shortest F wave latency 130% of the upper limit of normal or absence of
F waves all after 1620 stimuli. CMAP amplitude on distal stimulation of at least 05 mV
4. Normal sensory-nerve conduction in arm segments with motor conduction block.
Normal SNAP amplitudes on distal stimulation.
Denite MMN
111 on clinical criteria, 1 on laboratory criteria, and 1 and 4 on electrodiagnostic criteria
Probable MMN
13 and 611 on clinical criteria, 1 on laboratory criteria, and 2 and 4 on electrodiagnostic
criteria
Possible MMN
1 and 711 on clinical criteria, 2 or 3 on laboratory criteria, and 3 and 4 on
electrodiagnostic criteria
CMAP=compound muscle action potential; MCV=motor conduction velocity; DML=distal motor latency; SNAP=sensory
nerve action potential.
45
Review
recording in seven patients with MMN. Except for
intermediate-sized bres with thin myelinwhich could
have represented previous remyelinationparanodal
demyelination, internodal demyelination, and onion-bulb
formation were not found.
95
Although these ndings
suggest that axonal pathology is more prominent than
demyelinating pathology in MMN, they do not explain the
nding of conduction block on nerve-conduction studies
and the rapid response to intravenous immunoglobulin in
patients with MMN. The nding that, unlike CIDP,
inammatory cellular inltrates are sporadic in MMN
implies that the two disorders are unlikely to share
underlying disease mechanisms.
92,9496
The ndings in
biopsied sural nerves from patients with MMN were
either normal or showed mild axonal degeneration, mild
demyelination, or both, which is consistent with the
infrequent sensory impairment in patients with MMN.
11,97
Immunopathology
The positive response to immunomodulating treatment,
the nding of anti-GM1 in 2080% of patients with
MMN,
4,12,21,28,40,45,77
and the expression of GM1 on axon and
myelin membranes
77,98101
suggest that anti-GM1 are
pathogenetic in MMN. In this context, differences in the
fatty-acid and long-chain-base composition of peripheral-
nerve ganglioside GM1 between sensory and motor
nerves, resulting in different afnities of anti-GM1, could
contribute to selective involvement of motor bres.
102104
Antibody-mediated demyelination or blocking of the
voltage-gated sodium channels at the node of Ranvier
was supported by the results of some invivo and invitro
animal experiments
105108
but not in others.
109112
Furthermore, anti-GM1 binding sites and voltage gated
sodium channels were not colocalised.
113
Moreover,
human IgM anti-GM1 modulate intracellular calcium
homoeostasis in neuroblastoma cells, probably owing to
activation of L-type voltage-gated calcium channels that
are also present in motor neurons.
114
Overall, these
experiments have not conrmed or excluded the
pathogeneticity of IgM GM1 antibodies in MMN. The
nding that distal motor-nerve conduction in mice was
blocked by serum samples from patients with or without
high GM1 antibody titres suggests that factors other than
GM1 antibodies may be pathogenetic in MMN.
115
Electrophysiology
Conduction block, the electrophysiological hallmark of
MMN, was thought to underlie weakness in MMN. Most
nerve-conduction studies of patients with MMN found
improvement in conduction block after initial and long-
term treatment with intravenous immuno-
globulin.
18,19,25,27,34,55,75,116118
The inability of nerve-
conduction studies to assess proximal nerve segments
might explain the lack of improvement in conduction
block in some patients. Conduction block might cause
weakness that could, at least partly, be reversed by
intravenous immunoglobulin. In 39 patients with
MMN, long nerves had more segments with conduction
block owing to a random distribution of block in arm
nerves.
23
Furthermore, distal CMAPs were commonly
low in long nerves. Together, these ndings suggest
length-dependent axonal degeneration due to the high
occurrence of conduction block in these nerves.
23
Electrophysiological studies in patients with MMN who
were treated with intravenous immunoglobulin raised
important questions about the causes of weakness in
MMN. Although muscle strength in patients with MMN
improves after intravenous immunoglobulin treatment,
it rarely recovers to normal.
2427,33,47,55,75,76,119,120
Irreversible
weakness may be caused by irreversible conduction block
or axonal degeneration. Many observations suggest that
axonal degeneration contributes to weakness in patients
with MMN. Atrophic muscles, low distal CMAP
amplitudes on nerve-conduction studies, and ndings of
denervation and re-innervation on needle electro-
myography are all found in patients with MMN, even in
those with a short disease duration.
11,22,23,33,75
In a study of
patients with MMN who had never received intravenous
immunoglobulin treatment, a longer disease duration
was not only associated with more segments with
conduction block, but also with more nerves with low
distal CMAP amplitudes, the latter being consistent with
progressive axonal degeneration.
32
Weakness due to
progressive axonal degeneration was suggested to
underlie the less pronounced response to initial (or long-
term) intravenous immunoglobulin treatment for
patients with a long disease duration.
68
Three long-term
follow-up studies of patients on intravenous
immunoglobulin maintenance treatment showed a mild
decrease in muscle strength as well as continuing axonal
degeneration, measured by distal CMAP amplitude.
33,121,122
However, in a study that used a high monthly
maintenance dose of intravenous immunoglobulin the
results were contrasting: weakness was not progressive,
and distal CMAP amplitude did not suggest continuing
axonal degeneration.
75
To assess the independent contributions of conduction
block and axon loss to chronic progressive weakness,
we
73
did a multivariate analysis of 20 patients with MMN
who were receiving long-term intravenous immuno-
globulin treatment. Axon loss, and not conduction block,
had the strongest relation to weakness, whereas
conduction block alone had the strongest relation to
axon loss.
73
These ndings suggest that intravenous
immunoglobulin treatment affects reversible
conduction block but when conduction block is
irreversible the affected axons eventually degenerate
despite continuous intravenous immunoglobulin
treatment.
Generally, conduction block occurs when the action
current at one node does not induce a sufciently large
depolarisation at the next node to generate an action
potential, either because the current available is low or
because high current is needed.
123
The nding that
314 http://neurology.thelancet.com Vol 4 May 2005
Review
conduction block and demyelinative slowing were
independently related to each other in the arm nerves of
patients with MMN, and the nding of demyelination at
the site of conduction block on most biopsy studies,
suggests that conduction block results from a primary
demyelinating process.
73
In animal experiments,
paranodal demyelination impaired saltatory conduction;
the current available for depolarisation was low because
the outward capacitive sodium current, which leads to
depolarisation of the node to be activated, was dissipated
over the node and the adjacent damaged paranodal
region.
124,125
The period to depolarise the node to
threshold for an action potential will be longer when
moderate amounts of current are lost, yielding
conduction slowing. With severe loss of current, there
will be insufcient current to attain the threshold for an
action potential, yielding conduction block.
123
The loss of
current may be aggravated when demyelination exposes
paranodal or internodal potassium channels. Motor
axons in arm nerves have a more prominent slow
potassium conductance than motor axons in leg
nerves.
126
These differences in conductances could
contribute to the greater tendency of motor axons in arm
nerves to develop conduction block.
23,126,127
The mechanism that underlies axon loss in MMN is
poorly understood. A common disease mechanism that
leads to conduction block in some axons and
degeneration of other axons could explain the
independent relation between axon loss and conduction
block. A common disease mechanism is supported by
pathological studies showing that the antibodies to the
ganglioside GM1 bind to epitopes of the nodal axolemma
and paranodal myelin, possibly leading to conduction
block and axon loss, and to epitopes of spinal-cord motor
neurons, possibly leading to axon loss.
45,105,113,123
Alternatively, the association between axon loss and
conduction block might suggest that an axon will
eventually degenerate if a process resulting in conduction
block affects it. This mechanism is supported by
excitability measurements that showed axonal
hyperpolarisation adjacent to sites with conduction block.
Hyperpolarisation was thought to be secondary to intra-
axonal sodium accumulation at the site with conduction
block, caused by low activity of the sodium/potassium
pump.
128,129
An animal study of inammatory
demyelination showed that sodium accumulation leads to
intra-axonal calcium accumulation due to passive reversal
of the sodium/calcium exchanger.
130
An animal study of
inammatory demyelination supported this mechanism,
showing that blockade of sodium channels or
sodium/calcium exchanger prevented axonal
degeneration.
131
Treatment
The hypothesis that MMN is an immune-mediated
neuropathy has led to trials of several immunological
treatments. By contrast with CIDP, prednisolone and
plasma exchange were ineffective in most patients and
were even associated with clinical worsening in some
patients with MMN.
4,21,28,30,34,36,39,5458,76,116,120,132137
Of the
immunosuppressants, only high-dose cyclophosphamide
seems to be effective.
4,30,54,76
Unfortunately, the substantial
side-effects of cyclophosphamide, especially the risk of
neoplasia, restrict its use in patients with MMN.
Many open studies have shown that intravenous
immunoglobulin has a benecial effect.
1921,31,34,44,55,56,58,
67,75,76,90,116,117,138140
The efcacy of this treatment in MMN
was conrmed in four double-blind placebo-controlled
trials.
2427
The treatment was effective within a week, but
because the effect lasted only a few weeks, maintenance
treatment was needed to maintain the effect on muscle
strength in most patients.
19,33,117,120,122
Side-effects were
minor; the most disabling were skin changes (eczema)
on the hands and trunk.
141,142
Maintenance of intravenous immunoglobulin
treatment is expensive, and many patients nd the
frequent infusions onerous, but no alternative treatment
is available. Therefore, long-term studies are important.
We assessed the effects over 48 years in 11 patients
with MMN.
33
Muscle strength improved substantially
within 3 weeks of the start of treatment, and at the last
follow-up assessment muscle strength was better than
before treatment, even though it decreased slightly
during the follow-up period (gure 2). The treatment did
not induce remission in any of our patients; when it was
stopped, weakness progressed substantially. A study of
ten patients on maintenance treatment with intravenous
immunoglobulin over 512 years showed that the
effectiveness tended to decrease when treatment was
continued over a long period, even when the dose was
increased.
122
During the rst few years of maintenance
treatment, the response could be restored by increasing
the dose, whereas later an increase in dose was only
partially effective. However, in another study, a high
monthly maintenance dose of immunoglobulin was
shown to improve muscle strength and functional
disability during long-term follow-up.
75
Study of the
efcacy of various long-term doses with a double-blind
design is needed.
Natural course
Because most patients with MMN respond to
intravenous immunoglobulin treatment, a prospective
study on the natural course of MMN without any
treatment is not feasible. Two retrospective studies on
the natural course of MMN have been published; both
reported a slowly progressive course.
22,32
Step-wise
31,55
and
spontaneously remitting
2,19
disease courses have also
been described but are less common than the slow
progressive course. In a study of 38 patients with MMN,
we
32
showed that disease duration and disease severity
are related. Patients who responded to initial intravenous
immunoglobulin treatment had a disease duration of up
to 24 years and could have severe weakness. Lack of
http://neurology.thelancet.com Vol 4 May 2005 315
Review
response to intravenous immunoglobulin was not
associated with arm or leg involvement, muscle strength,
disability, or electrophysiological variables. Nobile-Orazio
and colleagues
68
showed that the response to initial
intravenous immunoglobulin treatment was less
pronounced for patients with a longer disease duration. A
continuing immunological process might cause
progression of weakness in MMN, and early treatment
could prevent future progression of weakness and
disability in patients with MMN. Although the overall
prognosis of patients with MMN seems to be better than
that of patients with lower-motor-neuron disease, most
patients with MMN have poor dexterity in manual tasks
that are a part of daily life.
22,32
Some patients are disabled
by fatigue;
70
in our opinion this symptom has been
underestimated in patients with MMN and needs further
study. Death after several years with the disease has been
reported in only two patients,
35,143
whereas in others, death
was related to concomitant diseases.
38,40
Conclusion
In the two decades since MMN was rst reported, clinical
and electrophysiological studies have led to advances in its
diagnosis and treatment. The clinical presentation of
MMN mimics that of lower-motor-neuron disease,
whereas conduction block on motor-conduction studies
differentiates between the two. The nding that
conduction block presents in patients with MMN
suggests that nerve conduction should be extensively
studied in every patient with a lower-motor-neuron
syndrome until conduction block is found to identify
patients who might respond favourably to
immunomodulating treatment. In MMN, but not in
lower-motor-neuron disease, high doses of intravenous
immunoglobulin produce rapid but unsustained
improvement in most patients. Although expensive,
repeated intravenous immunoglobulin treatment is
effective in maintaining remission and slowing
progression of weakness, according to the results of most
studies. Despite pathological and immunological studies,
the pathogenesis of MMN and the mechanism by which
immunoglobulin is effective are poorly understood. Most
evidence suggests that conduction block results from a
primary demyelinating process and that axonal
degeneration in MMN is related to it. Most likely,
intravenous immunoglobulin treatment affects reversible
conduction block whereas axonal degeneration continues
despite intravenous immunoglobulin treatment. Future
research on pathogenetic mechanisms is needed so that
novel treatment strategies for MMN can be developed.
Authors contributions
J-THVA, JHJW, and LVdB planned the review. J-THvA, RMVdB-V, and
LVdB researched relevant research papers. All authors contributed to
the writing of the review.
Conicts of interest
LVdB has received research grants and honoraria for lecturing from
companies that produce intravenous gammaglobulins, including
Baxter, Laboratoire Francais du fractionnement et des biothechnologies,
ZLB Bioplasma Belgium, and Sanguin.
Role of the funding source
A grant from the Prinses Beatrix Fonds supported this review.
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105
100
95
90
85
80
75
0
0 01 1 2 3 4 5
Duration of IVIg treatment (years)
Patient
1
2
3
4
5
6
7
8
9
10
11
Mean slope
M
R
C

s
u
m


s
c
o
r
e
6 7 8
Figure 2: Muscle strength of 11 patients with MMN during maintenance with intravenous immunoglobulin
treatment
Sum score of muscle strength was measured according to the Medical Research Council (MRC) criteria in ve
muscle groups in both arms and in ve muscle groups in both legs, yielding a maximum score of 100. 0=before the
start of intravenous immunoglobulin treatment; 01=after the rst full course of intravenous immunoglobulin;
18=during and after follow-up.
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